Process for preparing oxazolidine protected aminodiol compounds useful as intermediates to Florfenicol

ABSTRACT

An improved method of preparing oxazolidine protected aminodiol compounds is disclosed. These compounds are useful intermediates in processes for making Florfenicol.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a non-provisional application that claims priorityunder 35 U.S.C. § 119(e) of provisional application U.S. Ser. No.60/714,685 filed Sep. 7, 2005, the contents of which are herebyincorporated by reference in their entireties.

TECHNICAL FIELD

The present invention relates generally to a new process for preparingoxazolidine protected aminodiol compounds. These compounds are usefulintermediates in the process for making Florfenicol.

BACKGROUND OF THE INVENTION

Florfenicol is a broad spectrum antibiotic of Formula I

It has wide spread application in veterinary medicine for the treatmentof both Gram positive and Gram negative bacteria as well as rickettsialinfections. Florfenicol is also known as[R—(R*,S*)]-2,2-Dichloro-N-[1-(fluoromethyl)-2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl]acetamide.

Commonly-assigned U.S. Pat. No. 5,663,361, the disclosure of which isincorporated herein by reference, describes the synthesis of Florfenicolintermediates and their use in processes for making Florfenicol. Theprimary advantage discussed therein is that the process eliminated theprior art's requirement to isolate the aminodiol sulfone (ADS) from thereaction vessel before proceeding with the Florfenicol synthesis.

More recently, U.S. Patent 2005/0075506 A1 described a process forpreparing a compound of Formula II that is useful as an intermediate inthe synthesis of Florfenicol.

The process called for reacting the hydrochloride salt of an opticallypure aminodiol compound of Formula III with acetone followed by acetylchloride to give a compound of Formula II. The compound of Formula II isthen reacted further to give Florfenicol of Formula I.

A major drawback of the process disclosed in 2005/0075506 A1 is the useof the aminodiol starting material of Formula III. The aminodiolcompound of Formula III is expensive. It is also difficult to isolateand handle due to its amphoteric nature.

Another major drawback of the process disclosed in 2005/0075506 A1 isthe requirement to hydrolyze the oxazolidine and the N-acetyl group ofFormula IXa;

to generate a compound of Formula Xa;

followed by acylating, with a second N-acylating agent, to form acompound of Formula I.

The present invention addresses these shortcomings and providesalternative methods of preparing useful intermediates included in thesynthesis of Florfenicol.

SUMMARY OF THE INVENTION

In one embodiment, the present invention includes a process forpreparing an oxazolidine protected aminodiol compound of Formula V:

wherein:

R₁ is hydrogen, methylthio, methylsulfoxy, methylsulfonyl,fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro,fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, or C₂₋₆ heterocyclic group;

R₂ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, aryl,or C₂₋₆ heterocyclic group;

R₃ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, arylor C₂₋₆ heterocyclic group; and

R₄ is hydrogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, benzyl,phenyl or C₁₋₆ phenylalkyl group, where the phenyl ring may besubstituted by one or two halogens, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

In another preferred embodiment, the present invention includes aprocess for preparing an oxazolidine protected aminodiol compound ofFormula XII:

wherein:

R₁, R₂ and R₃ are as defined above; and

R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ dihaloalkyl, C₁₋₆trihaloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cyclohaloalkyl, C₃₋₈cyclodihaloalkyl, C₃₋₈ cyclotrihaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, C₂₋₆ heterocyclic, benzyl,phenyl or phenyl alkyl where the phenyl ring may be substituted by oneor two halogens, C₁₋₆ alkyl or C₁₋₆ alkoxy. Preferably, R₇ is CH₂Cl,CHCl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.

In one embodiment, the process includes the steps of:

a) reacting a compound of Formula VI:

wherein:

R₁ is as defined above and R₅ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,benzyl, phenyl or C₁₋₆ phenylalkyl, in a vessel with a reducing agent inan alcoholic solvent to form an aminodiol compound of Formula VII:

wherein:

R₁ is as defined above;

b) reacting the aminodiol compound of Formula VII in the vessel withoutisolation (i.e., in situ) with an oxazolidine forming reagent to form acompound of Formula VIII:

wherein R₁, R₂ and R₃ are as defined above; and

c) reacting the compound of Formula VIII in the vessel without isolation(i.e., in situ) with a first N-acylating agent to form an oxazolidineprotected aminodiol compound of Formula V.

In another preferred embodiment, the process includes the steps of:

a) reacting a compound of Formula VI in a vessel with a reducing agentin an alcoholic solvent to form an aminodiol compound of Formula VII;

b) reacting the aminodiol compound of Formula VII in the vessel withoutisolation (i.e., in situ) with an oxazolidine forming agent to form thecompound of Formula VIII;

c) reacting the compound of Formula VIII in the vessel without isolation(i.e., in situ) with an N-acylating agent to form an oxazolidineprotected aminodiol compound of Formula XII;

d) fluorinating the compound of Formula XII with a fluorinating agent inthe presence of an organic solvent to obtain the compound of FormulaXIII:

wherein R₁, R₂, R₃ and R₇ are as defined above;

e) selectively hydrolyzing the compound of Formula XIII with an acid orbase catalyst to form the compound of Formula XI:

wherein R₁ and R₇ are as defined above; and

f) if necessary, purifying the compound of Formula XI with a mixture ofa C₁₋₁₀ alkyl mono, di or tri alcohol and water to form the purecompound of Formula XI.

Applicants have now surprisingly found significant processing advantagesfor forming the oxazolidine protected aminodiol compounds of Formula Vand Formula XII. The compounds of Formula V, or specifically Formula II,are obtained when an ester precursor to the aminodiol free base compoundof Formula III are used as starting materials. Such esters generallycorrespond to Formula VI, and the ester of Formula IV is oneparticularly preferred ester:

The use of the esters of Formulas IV and VI generates the expensive freebase starting material of Formula III in situ, thereby eliminating theneed to isolate this difficult to isolate compound. Yield losses for thefree base starting material of Formula III due to isolation are thuseliminated with resulting increased yield and lower cost for theoxazolidine protected aminodiol compound of Formula V, or specificallythe compound of Formula II, or in the more preferred embodiment theoxazolidine protected aminodiol compound of Formula XII. Applicants havealso found ways to utilize the compound of Formula IV with moreefficient and cost-saving processes. The present invention thus has theadvantage of being an efficient and economical process for preparingFlorfenicol, its analogs and oxazolidine intermediates related thereto.

DETAILED DESCRIPTION OF THE EMBODIMENTS

When utilized in the present specification and in the appended claims,the terms listed herein below, unless otherwise indicated, are definedas follows:

The term “alcoholic solvent” includes C₁ to C₁₀ alcohols such asmethanol and ethanol and mixtures thereof, C₂ to C₁₀ dialcohols such asethylene glycol and C₁ to C₁₀ trialcohols such as glycerin.Alternatively, the alcoholic solvent can be admixed with any suitablecosolvent. Such cosolvents can include other solvents which are misciblewith the alcoholic solvent such as C₄ to C₁₀ alkanes, aromatic solventssuch as benzene, toluene, xylenes, halobenzenes such as chlorobenzene,and ethers such as diethylether, tert-butylmethylether, isopropyletherand tetrahydrofuran, or mixtures of any of the above solvents orcosolvents.

The term “alkyl” means a straight or branched alkyl such as methyl,ethyl, propyl, or sec-butyl. Alternatively, the number of carbons inalkyl may be specified. For example, “C₁ to C₆ alkyl” means an “alkyl”as described above containing 1 to 6 carbon atoms. “Haloalkyl” means an“alkyl” as described above wherein one or more hydrogens are replaced byhalo.

The term “aryl” means phenyl, or phenyl substituted by C₁ to C₆ alkyl orhalo.

“Substituted benzyl” means benzyl substituted by C₁ to C₆ alkyl or halo.

The term “halo” means fluoro, chloro, bromo or iodo.

The term “halo aryl” means phenyl substituted by halo.

In one aspect of the invention, there is provided a process forpreparing an oxazolidine protected aminodiol compound of Formula V:

wherein:

R₁ is hydrogen, methylthio, methylsulfoxy, methylsulfonyl,fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro,fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, or C₂₋₆ heterocyclic group;

R₂ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, aryl,or C₂₋₆ heterocyclic group;

R₃ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, arylor C₂₋₆ heterocyclic group; and

R₄ is hydrogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, benzyl,phenyl or C₁₋₆ phenylalkyl group, where the phenyl ring may besubstituted by one or two halogens, C₁₋₆ alkyl or C₁₋₆ alkoxy.

The compounds corresponding thereto are useful intermediates in theformation of Florfenicol and related compounds.

One preferred process corresponding to the invention includes the stepsof:

a) reacting a compound of Formula VI:

wherein:

R₁ is as defined above and R₅ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,benzyl, phenyl or C₁₋₆ alkylphenyl, in a vessel with a reducing agent inan alcoholic solvent to form an aminodiol compound of Formula VII:

wherein R₁ is as defined above;

b) reacting the aminodiol compound of Formula VII in the vessel withoutisolation (i.e., in situ) with an oxazolidine forming reagent to form acompound of Formula VIII:

wherein R₁, R₂, R₃ and R₄ are as defined above; and

c) reacting the compound of Formula VIII in the vessel without isolation(i.e., in situ) with a first N-acylating agent to form an oxazolidineprotected aminodiol compound of Formula V:

wherein R₁, R₂, R₃ and R₄ are as defined above.

Within the general process described above, there are certain currentlypreferred aspects of the invention:

R₁ is methylthio, methylsulfoxy, or methylsulfonyl. More preferably, R₁is methylsulfonyl;

R₂ and R₃ are hydrogen, methyl, ethyl or propyl. More preferably, R₂ andR₃ are methyl;

R₄ is a methyl, ethyl, propyl or isopropyl group. More preferably, R₄ ismethyl; and

R₅ is methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, or pentyl. Thecompound of Formula IV is commercially available. Alternative compoundscorresponding to Formula VI can be prepared using standard organicsynthetic techniques without undue experimentation.

One preferred ester compound corresponding to Formula VI is

In another aspect of the invention, the ester compound of Formula VI is

In still further aspects, the esters correspond to:

wherein R₅ is as defined above.

In a more preferred embodiment when Florfenicol is the desired endproduct, the compound corresponding to Formula VI is the compound ofFormula IV.

As mentioned above, the first part of the process calls for reacting acompound of Formula VI in a reaction vessel with a reducing agent. Forpurposes of the present invention, the term “reaction vessel” shall beunderstood to mean a container known to those of ordinary skill which iscapable of holding the reactants and allowing the reaction step toproceed to completion. The size and type of vessel will, of course,depend upon the size of the batch and the specific reactants selected.

A wide range of suitable reducing agents can be employed in carrying outthe process of the invention. A non-limiting list of suitable reducingagents include NaBH₄, KBH₄, Ca(BH₄)₂, and LiBH₄ and mixtures thereofwhen an alcoholic solvent is used. The alcoholic solvent can also be oneof many art-recognized solvents but some preferred solvents includemethanol, ethanol, propanol, isopropanol, butanol and pentanol andmixtures thereof. One preferred reducing agent is KBH₄.

The molar ratio of reducing agent, such as KBH₄, to the compound ofFormula IV is between about 1:1 and about 2:1. Preferably, when thereducing agent is KBH₄, the molar ratio of KBH₄ to the compound ofFormula IV is about 1.5:1 and the preferred solvent is methanol. Thisreduction can be carried out at a temperature of about 30° C. to about80° C. in about 8 hours. Preferably, the temperature is below 60° C. andthe time for the reaction to reach completion is under 6 hours.

In an alternative aspect of the invention, the artisan can use reducingagents such as LiAlH₄ or NaAlH₄ when anhydrous conditions are desired.In such situations, solvents like ether or tetrahydrofuran can be used.

Once the aminodiol compound corresponding to Formula VII has been made,it is reacted, preferably in the same vessel (i.e., in situ), with anoxazolidine forming reagent such as formaldehyde, acetone,2-methoxypropene, 2,2-dimethoxypropane, 2,2-diethoxypropane and mixturesthereof, under conditions such as those set forth in the examples tomake a compound of Formula VIII. One preferred aminodiol compoundcorresponding to Formula VII is

In a preferred embodiment when Florfenicol is the desired end product,the compound corresponding to Formula VIII is the compound:

In a preferred embodiment, the methanol solvent is removed bydistillation and replaced with another solvent designated herein as anoxazolidine forming solvent such as toluene, xylene, hexane or a mixturethereof. The preferred oxazolidine forming solvent is toluene. The ratioof the oxazolidine forming solvent to methanol is about 0.5:1 to 3:1with the preferred ratio of about 1:1. An oxazolidine forming reagentsuch as formaldehyde, acetone, 2-methoxypropene, 2,2-dimethoxypropane,2,2-diethoxypropane and mixtures thereof is then added. One preferredoxazolidine forming reagent is acetone which is added in a ratio totoluene of about 0.5:1 to 3:1 with the preferred ratio of about 1:1. Thereaction runs to completion to form the oxazolidine compound of FormulaVIII over about 12-18 hours in the presence of a base designated hereinas an oxazolidine promoting base such as potassium carbonate, sodiumcarbonate, trimethylamine or triethylamine. A preferred base ispotassium carbonate or triethylamine. The oxazolidine forming reactioncan be carried out at a temperature of about 65-85° C.

It is preferred that the compound of Formula VIII remain in the samevessel after completion of the reaction step when the first N-acylatingagent is added. The nomenclature “first,” “second” and “third” are usedfor describing the (1) N-acylating (first) agents so as to distinguishthe agents used for making the oxazolidine protected aminodiol compoundsof Formula V, from the (2) N-acylating agents (second) which are used inthe formation of the compounds of Formula XI after the intermediate ofFormula X has been formed, from the (3) N-acylating agents (third) usedduring the process to form the oxazolidine protected aminodiol compoundsof Formula XII. Thus, some preferred first N-acylating compounds are ofthe formula R₆COR₄

wherein:

R₄ is hydrogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, benzyl,phenyl or C₁₋₆ phenylalkyl group, where the phenyl ring may besubstituted by one or two halogens, C₁₋₆ alkyl or C₁₋₆ alkoxy; and

R₆ is halo, or C₁₋₆ alkoxy.

Some more preferred first acylating agents include acetyl chloride,acetyl bromide, propionyl chloride, propionyl bromide, butyl chloride,methyl chloroformate, ethyl chloroformate, propyl chloroformate andmixtures thereof.

In a preferred embodiment when Florfenicol is the desired end product,the compound corresponding to Formula V is the compound:

In a preferred embodiment, a base such as potassium carbonate, sodiumcarbonate, trimethylamine or triethylamine is added in a molarequivalent ratio to the compound of Formula VII of about 1:1 to 1:3. Thepreferred base is potassium carbonate or triethylamine and the preferredmolar equivalent ratio is about 1.1 to 1. The preferred firstN-acylating agent acetyl chloride is added in a molar ratio to thecompound of Formula VII of about 1:1 to 3:1 with the preferred ratiobeing 1.1:1. Reaction temperature is about 20-30° C. and the reactioncompletes in about 2-4 hours.

After the oxazolidine protected aminodiol compound of Formula V has beenprepared, it can be used in the synthesis of Florfenicol and relatedcompounds. Thus, in a further aspect of the invention, the inventiveprocess continues by fluorinating the compound of Formula V:

wherein R₁, R₂, R₃ and R₄ are as defined above, with a fluorinatingagent in the presence of an organic solvent to obtain a compound ofFormula IX:

wherein R₁, R₂, R₃ and R₄ are as defined above.

In one preferred aspect of this embodiment when Florfenicol is thedesired end product, the compound corresponding to Formula IX isspecifically:

Suitable fluorinating agents include, without limitation,N-(2-chloro-1,1,2-trifluoroethyl)diethylamine,N-(2-chloro-1,1,2-trifluoroethyl)dimethylamine,N-(2-chloro-1,1,2-trifluoroethyl)dipropylamine,N-(2-chloro-1,1,2-trifluoroethyl)pyrrolidine,N-(2-chloro-1,1,2-trifluoroethyl)-2-methylpyrrolidine,N-(2-chloro-1,1,2-trifluoroethyl)-4-methylpiperazine,N-(2-chloro-1,1,2-trifluoroethyl)-morpholine,N-(2-chloro-1,1,2-trifluoroethyl)piperidine,1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, (Diethylamino)sulfurtrifluoride, Bis-(2-methoxyethyl)aminosulfur trifluoride,N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) andmixtures thereof. One preferred fluorinating agent isN,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine.

The molar ratio of the fluorinating agent such asN,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine to the compoundaccording to Formula V is between about 1:1 and about 2:1. Preferably,the molar ratio of the N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamineto the compound of Formula V is about 1.5:1. The fluorinating step canbe carried out at a temperature of from about 80° C. to about 110° C.and at a pressure of about 60 psi.

The organic solvent used during the fluorinating step is preferably1,2-dichloroethane, methylene chloride, chloroform, chlorobenzene,chlorinated hydrocarbons or mixtures thereof. A more preferred organicsolvent is methylene chloride.

After the compound of Formula IX has been made, it is hydrolyzed withacid to form the compound of Formula X:

wherein R₁ is as defined above, preferably, R₁ is CH₃SO₂.

The acid used in this part of the process can be an inorganic acid likeaqueous hydrochloric acid, sulfuric acid, or phosphoric acid or anorganic acid like methanesulfonic acid. The hydrolyzing step ispreferably carried out by heating the compound of Formula IX with 6Naqueous hydrochloric acid at a temperature of from about 90° C. to about105° C. for about 60 minutes. Other suitable hydrolyzing steps will beapparent to those of ordinary skill.

In one preferred aspect of this embodiment when Florfenicol is thedesired end product, the compound corresponding to Formula X is:

After hydrolysis has been completed, the compound of Formula X isreacted without isolation (i.e., in situ) with a second N-acylatingagent to make compounds of Formula XI:

wherein R₁ is the same as above, preferably CH₃SO₂; and

R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ dihaloalkyl, C₁₋₆trihaloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cyclohaloalkyl, C₃₋₈cyclodihaloalkyl, C₃₋₈ cyclotrihaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, C₂₋₆ heterocyclic benzyl,phenyl or phenyl alkyl where the phenyl ring may be substituted by oneor two halogens, C₁₋₆ alkyl or C₁₋₆ alkoxy. Preferably, R₇ is CH₂Cl,CHCl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃. Thus, one preferredcompound of Formula XI is:

wherein R₇ is as defined above.

In one preferred aspect of this embodiment when Florfenicol is thedesired end product, the compound corresponding to Formula XI is thecompound of Formula I:

Suitable second N-acylating compounds are of the formula R₈COR₇, whereinR₇ is the same as that described above and R₈ is OH, halo or C₁₋₆alkoxy. Some more preferred second N-acylating agents includedichloroacetic acid or a reactive derivative thereof. A non-limitinglist includes reagents such as methyldichloroacetate,ethyldichloroacetate, or dichloroacetylchloride.

The second N-acylation step is preferably carried out by reacting thecompound of Formula X in methanol with methyldichloroacetate at atemperature of from about 20° C. to about 30° C. for about 12 hours.

After the compound of Formula XI is made and if necessary, the compoundof Formula XI can optionally be purified by heating in a mixture of analkyl mono, di or tri alcohols and water. The alcohols in this part ofthe process can be C₁₋₁₀ monoalcohols, C₁₋₁₀ dialcohols and C₁₋₁₀trialcohols and mixtures thereof. A non-limiting list of the C₁₋₁₀monoalcohols includes methanol, ethanol, propanol, isopropanol, butanol,sec-butanol, t-butanol and pentanol. One preferred C₁₋₁₀ monoalcohol isisopropanol. A non-limiting list of the C₁₋₁₀ dialcohols includesethylene glycol, propylene glycol and butylene glycol of which propyleneglycol is preferred. Glycerin is the preferred C₁₋₁₀ trialcohol. A C₁₋₁₀monoalcohol is preferred for the purification. One most preferred C₁₋₁₀monoalcohol is isopropanol.

The ratio of alcohol, such as isopropanol, to water is between 1:5 and5:1. Preferably, when the alcohol is isopropanol, the ratio ofisopropanol to water is 1:1. The compound of Formula XI is dissolved ina 1:1 mixture of isopropanol and water heated to the reflux point of themixture. The solution is clarified by filtration with active carbon anda filter aid, then cooled to about 10-30° C. and the purified compoundof Formula XI crystallizes from solution. Preferably, the solution iscooled to about 20-25° C. and the purified compound of Formula XIcrystallizes from solution.

In a preferred embodiment when Florfenicol is the desired end product,the purified compound corresponding to Formula XI is the compound ofFormula I.

In another preferred embodiment, the process corresponding to theinvention includes the steps of:

a) reacting a compound of Formula VI in a vessel with a reducing agentin an alcoholic solvent to form an aminodiol compound of Formula VII;

b) reacting the aminodiol compound of Formula VII in the vessel withoutisolation (i.e., in situ) with an oxazolidine forming agent to form acompound of Formula VIII;

c) reacting the compound of Formula VIII in the vessel without isolation(i.e., in situ) with a third N-acylating agent to form an oxazolidineprotected aminodiol compound of Formula XII:

wherein:

R₁, R₂, R₃ and R₇ are as defined above. Preferably, R₇ is CH₂Cl, CHCl₂,CCl₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃;

d) fluorinating the compound of Formula XII with a fluorinating agent inthe presence of an organic solvent to obtain a compound of Formula XIII:

wherein R₁, R₂, R₃ and R₇ are as defined above;

e) selectively hydrolyzing the compound of Formula XIII with an acid orbase catalyst to form the compound of Formula XI; and

f) if necessary, purifying the compound of Formula XI with a mixture ofa C₁₋₁₀ alkyl mono, di or tri alcohol and water to form the purecompound of Formula XI.

In the preferred embodiment described above, there are certain preferredaspects of the invention. One preferred aspect is that after thecompound of Formula VIII is made it is reacted preferably in the samevessel (i.e., in situ) with a suitable third N-acylating compound. Somepreferred third N-acylating compounds are of the formula R₆COR₇ whereinR₆ and R₇ are as defined above. In a preferred embodiment, R₆ is Cl andR₇ is CH₂Cl, CHCl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.

Some preferred third N-acylating agents include alkylhaloacetic acidderivatives. A non-limiting list includes reagents such asmethyldichloroacetate, ethyldichloroacetate, dichloroacetylchloride,methylchloroacetate, ethylchloroacetate, chloroacetylchloride,methyltrichloroacetate, ethyltrichloroacetate, trichloroacetylchloride,methyldifluoroacetate, ethyldifluoroacetate, difluoroacetylchloride,methylfluoroacetate, ethylfluoroacetate, fluoroacetylchloride,methyltrifluoroacetate, ethyltrifluoroacetate, trifluoroacetylchloride,dichloroacetylbromide, difluoroacetylbromide, acetylchloride andacetylbromide.

In a preferred embodiment when Florfenicol is the desired end product,the compound corresponding to Formula XII is the compound of FormulaXIIa:

In a preferred embodiment, a base such as potassium carbonate, sodiumcarbonate, trimethylamine or triethylamine is added in a molarequivalent ratio to the compound of Formula VIIIa of about 1:1 to 1:3.The preferred base is potassium carbonate or triethylamine and thepreferred molar equivalent ratio is about 1.1 to 1. The preferredN-acylating agent dichloroacetyl chloride is added in a molar ratio tothe compound of Formula VIIIa of about 1:1 to 3:1 with the preferredratio being 1.1:1. Reaction temperature is about 20-30° C. and thereaction completes in about 2-4 hours.

After the oxazolidine protected aminodiol compound of Formula XII hasbeen prepared, it can be used in the synthesis of Florfenicol andrelated compounds. Thus, in a further aspect of the invention, theinventive process continues by fluorinating the compound of Formula XII:

wherein R₁, R₂, R₃ and R₇ are as defined above, with a fluorinatingagent, as previously defined, in the presence of an organic solvent, aspreviously defined, to obtain a compound of Formula XIII:

wherein R₁, R₂, R₃ and R₇ are as defined above.

In one preferred aspect of this embodiment when Florfenicol is thedesired end product, the compound corresponding to Formula XIII isspecifically the compound of Formula XIIIa:

After the compound of Formula XIII has been made, it is selectivelyhydrolyzed with acid or base catalyst to form the compound of FormulaXI.

A wide range of acid catalysts can be employed in carrying out theprocess of the invention. A non-limiting list of suitable acid catalystsinclude inorganic acids like dilute aqueous hydrochloric acid, sulfuricacid, or phosphoric acid or organic acids like methanesulfonic acid orp-toluene sulfonic acid. One preferred acid catalyst is p-toluenesulfonic acid. Similarly, a wide range of basic catalysts can beemployed in carrying out the process of the invention. A non-limitinglist of suitable basic catalysts include inorganic bases such as LiOH,NaOH, KOH, Li₂CO₃, Na₂CO₃, K₂CO₃ or organic bases such as sodiummethoxide, sodium ethoxide, potassium methoxide and potassium ethoxide.One preferred basic catalyst is K₂CO₃. The selective hydrolyzing step ispreferably carried out be heating the compound of Formula XIII withp-toluene sulfonic acid in a mixture of an organic solvent and water ata temperature below 80° C. One preferred organic solvent is methylenechloride. Other suitable selective hydrolyzing steps will be apparent tothose of ordinary skill.

In one preferred aspect of this embodiment when Florfenicol is thedesired end product, the compound corresponding to Formula XI is thecompound of Formula I:

After the compound of Formula XI is made and if necessary, it canoptionally be purified by the process as described above. In a preferredembodiment when Florfenicol is the desired end product, the purifiedcompound corresponding to Formula XI is the compound of Formula I.

EXAMPLES

The following preparative examples of preferred novel derivatives serveto provide further appreciation of the invention but are not meant inany way to restrict the effective scope of the invention.

Example 1 Preparation of(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound II)

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate(Compound IV) (100 g, 0.3480 moles) in 500 mL of methanol reacts withpotassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C.to quantitatively yield(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (CompoundVII: R₁ is methylsulfonyl) (85.36 g, 0.3480 moles) in solution. Toluene(500 mL) and acetone (500 mL) replace methanol which distills off.Addition of potassium carbonate (6.9 g, 0.0696 moles) with heating at75-85° C. for 12-18 hours yields(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound VIII: R₁ is methylsulfonyl and R₂ and R₃ are methyl). Additionof potassium carbonate (19.0 g, 0.1914 moles) and acetyl chloride (30.0g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500mL) precipitates the crude product. Filtration, washing with water (250mL) then drying yields(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound II).

Example 2 Preparation of(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound II)

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate(Compound IV) (100 g, 0.3480 moles) in methanol (450 mL) reacts withpotassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C.to quantitatively yield(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (CompoundVII: R₁ is methylsulfonyl) (85.4 g, 0.3480 moles) in solution. Toluene(450 mL) and acetone (450 mL) replace methanol which distills off.Addition of triethylamine (8.8 g, 0.0870 moles) with heating at 70-80°C. for 12-18 hours yields(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound VIII: R₁ is methylsulfonyl and R₂ and R₃ are methyl). Additionof triethylamine (44.5 g, 0.4402 moles) and acetyl chloride (30.0 g,0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL)precipitates the crude product. Filtration, washing with water (200 mL)then drying yields(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound II).

Example 3 Preparation of(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound II)

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate(Compound IV) (100 g, 0.3480 moles) in tetrahydrofuran (500 mL) reactswith lithium aluminum hydride (16.0 g, 0.4224 moles) over 4-8 hours at60-70° C. to quantitatively yield(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (CompoundVII: R₁ is methylsulfonyl) (85.36 g, 0.3480 moles). Addition of ethylacetate (75 mL) destroys any excess lithium aluminum hydride. Additionof xylene (600 mL), 2-methoxypropene (37.6 g, 0.5220 moles), andp-toluenesulfonic acid monohydrate (6.6 g, 0.0348 moles) with agitationat 20-30° C. for 10-16 hours produces(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound VIII: R₁ is methylsulfonyl and R₂ and R₃ are methyl). Additionof triethylamine (81.3 g, 0.8039 moles) and acetyl chloride (30.0 g,0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (650 mL)precipitates the crude product. Filtration, washing with water (300 mL)then drying yields(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound II).

Example 4 Preparation of(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound V: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ is ethyl)

(2S,3R)-Methyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate(Compound VI: R₁ is methylsulfonyl and R₅ is methyl) (75 g, 0.2744moles) in 350 mL of methanol reacts with sodium borohydride (16.6 g,0.4390 moles) over 4-8 hours at 50-60° C. to quantitatively yield(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (CompoundVII: R₁ is methylsulfonyl) (67.31 g, 0.2744 moles) in solution. Additionof 20% hydrochloric acid and 2,2-dimethoxypropane (35.7 g, 0.3430 moles)with agitation at 25-35° C. for 3-5 hours then addition of xylene (650mL) and heating to 75-85° C. for a further 12-16 hours yields(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound VIII: R₁ is methylsulfonyl and R₂ and R₃ are methyl). Additionof triethylamine (52.1 g, 0.5145 moles) and propionyl chloride (31.7 g,0.3430 moles) at 20-25° C. for 2-4 hours then addition of water (625 mL)precipitates the crude product. Filtration, washing with water (300 mL)then drying yields(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)-phenyl]-1,3-oxazolidine(Compound V: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ isethyl).

Example 5 Preparation of(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl; R₂, R₃ and R₄ are methyl)

(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound II) (75 g, 0.2291 moles) in methylene chloride (525 ml) reactswith N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent)(76.7 g, 0.3437 moles) at 95-105° C. for about 4 hours. Cooling to20-25° C., addition to sodium hydroxide (6 g) in water (2500 mL),separation of the methylene chloride layer, distillation and replacementof methylene chloride by isopropanol (750 mL), precipitates the desiredproduct. Filtration, washing with water (100 mL) and isopropanol (75mL), then drying yields(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl; R₂, R₃ and R₄ are methyl).

Example 6 Preparation of(4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ isethyl)

(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound V: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ is ethyl)(70 g, 0.2050 moles) in methylene chloride (450 ml) reacts withN,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent)(73.2 g, 0.328 moles) at 95-105° C. for 2-4 hours. Cooling to 20-25° C.,quenching with 25% aqueous sodium hydroxide and water (2000 mL) andseparation of the methylene chloride layer gives a solution of(4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ isethyl) for use in the next step.

Example 7 Preparation of(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol)

(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl; R₂, R₃ and R₄ are methyl) (50.0 g,0.1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloricacid at 90 to 100° C. over about 1 hour. Adjusting the pH to greaterthan 12 by addition of sodium hydroxide and extraction with methylenechloride (500 mL) yields(1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol(Compound Xa) in solution. Methanol (100 mL) replaces methylene chloridewhich distills off. Addition of methyl dichloroacetate (65.1 g, 0.4554moles) and triethylamine (16.1 g, 0.1594 moles) with agitation for 12-16hours at 20-25° C. then addition of water (175 mL) and toluene (100 mL)precipitates the product. Filtration, washing with water (100 mL) andtoluene (175 mL) then drying yields(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methyl-sulfonyl)phenyl]-1-propanol(Florfenicol).

Example 8 Preparation of(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol)

(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl; R₂, R₃ and R₄ are methyl) (50.0 g,0.1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloricacid at 90 to 100° C. over about 1 hour. Adjusting the pH to greaterthan 12 by addition of sodium hydroxide and extraction with methylenechloride (500 mL) yields(1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol(Compound Xa) in solution. Addition of triethylamine (16.9 g, 0.1670moles) and dichloroacetyl chloride (24.6 g, 0.1670 moles) at 20-30° C.for 4-6 hours then removal of methylene chloride by distillation andreplacement by toluene (350 mL) and water (100 mL) precipitates theproduct. Filtration, washing with water (150 mL) and toluene (150 mL)then drying yields(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol).

Example 9 Purification of(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol)

(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol) (45 g, 0.1256 moles) dissolves in water (115 mL) andisopropanol (115 mL) at reflux. Cooling to 20-25° C., filtration of thesolids, washing with 1 to 1 water/isopropanol (50 mL) then drying givespure(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol).

Example 10 Preparation and Purification of(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol)

(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl; R₂, R₃ and R₄ are methyl) (50.0 g,0.1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloricacid at 90 to 100° C. over about 1 hour. Washing with methylene chloride(200 mL), adjusting the pH to greater than 12 by addition of sodiumhydroxide and extraction with methylene chloride (300 mL) yields(1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol(Compound Xa) in solution. Methanol (100 mL) replaces methylene chloridewhich distills off. Addition of methyl dichloroacetate (65.1 g, 0.4554moles) and triethylamine (16.1 g, 0.1594 moles) with agitation for 12-16hours at 20-25° C. then addition of water (175 mL) and toluene (100 mL)precipitates the crude product. Filtration, washing with water (100 mL)and toluene (174 mL) then dissolution in water (115 mL) and isopropanol(115 mL) at reflux, cooling to 20-25° C., filtration of the solids,washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol).

Example 11 Preparation and Purification of(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol)

Methylene chloride (450 mL) distills from a solution of(4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound IX: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ isethyl) (50.0 g, 0.1456 moles) after addition of water (300 mL)containing 20% hydrochloric acid and heating to 90-100° C. for 2-4hours. Adjusting the pH to greater than 12 by addition of sodiumhydroxide and extraction with methylene chloride (350 mL) yields asolution of(1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol(Compound Xa). Methanol (150 mL) replaces methylene chloride whichdistills off. Addition of methyl dichloroacetate (52.0 g, 0.3640 moles)and triethylamine (11.0 g, 0.1092 moles) with agitation for 12-16 hoursat 20-25° C. then addition of water (150 mL) and toluene (100 mL)precipitates the crude product. Filtration, washing with water (75 mL)and toluene (125 mL) then dissolution in water (50 mL) and isopropanol(100 mL) at reflux, cooling to 20-25° C., filtration of the solids,washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol).

Example 12 Preparation of(4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound XIIa)

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate(Compound IV) (100 g, 0.3480 moles) in 500 mL of methanol reacts withpotassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C.to quantitatively yield(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (CompoundVII: R₁ is methylsulfonyl) (85.36 g, 0.3480 moles) in solution. Toluene(500 mL) and acetone (500 mL) replace methanol which distills off.Addition of potassium carbonate (6.9 g, 0.0696 moles) with heating at75-85° C. for 12-18 hours yields(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound VIII: R₁ is methylsulfonyl and R₂ and R₃ are methyl). Additionof potassium carbonate (19.0 g, 0.1914 moles) and dichloroacetylchloride (56.4 g, 0.3828 moles) at 20-25° C. for 2-4 hours then additionof water (500 mL) precipitates the crude product. Filtration, washingwith water (250 mL) then drying yields(4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound XIIa).

Example 13 Preparation of(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound XIIIa)

(4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound XIIa) (81 g, 0.2050 moles) in methylene chloride (450 ml)reacts with N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (IshikawaReagent) (73.2 g, 0.328 moles) at 95-105° C. for 2-4 hours. Cooling to20-25° C., quenching with 25% aqueous sodium hydroxide and water (2000mL) and separation of the methylene chloride layer gives a solution of(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound XIIIa) for use as an intermediate for the next step in theprocess.

Example 14 Preparation of(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol)

(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine(Compound XIIIa) (60.5 g, 0.1519 moles) selectively hydrolyses inmethylene chloride (300 mL) and water (100 mL) containing p-toluenesulfonic acid at 60° C. over several hours. Removal of the methylenechloride by distillation and cooling to 20-25° C. precipitates theproduct. Filtration, washing with water (100 mL) and toluene (100 mL)then drying yields(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol(Florfenicol).

1. A process for preparing a compound of Formula XI:

wherein: R₁ is hydrogen, methylthio, methylsulfoxy, methylsulfonyl,fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro,fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, or C₂₋₆ heterocyclic group;and R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ dihaloalkyl, C₁₋₆trihaloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cyclohaloalkyl, C₃₋₈cyclodihaloalkyl, C₃₋₈ cyclotrihaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, C₂₋₆ heterocyclic, benzyl,phenyl or phenyl alkyl where the phenyl ring may be substituted by oneor two halogens, C₁₋₆ alkyl or C₁₋₆ alkoxy comprising: a) reacting acompound of Formula VI

wherein: R₁ is as defined above; R₅ is hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl, benzyl, phenyl or C₁₋₆ alkylphenyl, in a vessel with areducing agent in an alcoholic solvent to form an aminodiol compound ofFormula VII;

wherein R₁ is as defined above; b) reacting the aminodiol compound ofFormula VII in situ with an oxazolidine forming reagent to form acompound of Formula VIII

wherein: R₁ is as defined above; R₂ is hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ aralkyl, C₂₋₆ aralkenyl, aryl, or C₂₋₆ heterocyclic group; and R₃is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, aryl or C₂₋₆heterocyclic group; c) reacting the compound of Formula VIII in situwith a third N-acylating agent to form an oxazolidine protectedaminodiol compound of Formula XII

wherein: R₁, R₂, R₃ and R₇ are as defined above; d) fluorinating thecompound of Formula XII with a fluorinating agent in the presence of anorganic solvent to obtain a compound of Formula XIII

wherein: R₁, R₂, R₃ and R₇ are as defined above; and e) selectivelyhydrolyzing the compound of Formula XIII with an acid or base catalystto form a compound of Formula XI.
 2. The process of claim 1, wherein R₁is methylthio, methylsulfoxy, or methylsulfonyl.
 3. The process of claim2, wherein R₁ is methylsulfonyl.
 4. The process of claim 1, wherein R₂and R₃ are hydrogen, methyl, ethyl or propyl.
 5. The process of claim 4,wherein R₂ and R₃ are methyl.
 6. The process of claim 1, wherein R₅ ismethyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, or pentyl.
 7. Theprocess of claim 1, wherein the compound of Formula VI is


8. The process of claim 1, wherein the compound of Formula VI is


9. The process of claim 1, wherein the reducing agent is selected fromthe group consisting of NaBH₄, KBH₄, Ca(BH₄)₂, and LiBH₄ and mixturesthereof.
 10. The process of claim 9, wherein the reducing agent is KBH₄.11. The process of claim 10, wherein the molar ratio of KBH₄ to thecompound of Formula VI is between about 1:1 and 2:1.
 12. The process ofclaim 11, wherein the molar ratio of KBH₄ to the compound of Formula VIis about 1.5:1.
 13. The process of claim 9, wherein the reduction iscarried out at a temperature below 60° C.
 14. The process of claim 13,wherein the reduction is complete within 6 hours.
 15. The process ofclaim 1, wherein the alcoholic solvent is selected from the groupconsisting of methanol, ethanol, propanol, isopropanol, butanol,pentanol, ethylene glycol, glycerin and mixtures thereof.
 16. Theprocess of claim 15, wherein the solvent is methanol or ethanol.
 17. Theprocess of claim 16, wherein the solvent is methanol.
 18. The process ofclaim 1, wherein the compound of Formula VII is


19. The process of claim 1, wherein the oxazolidine forming solvent isselected from toluene, xylene, hexanes or mixtures thereof.
 20. Theprocess of claim 19, wherein the oxazolidine forming solvent is toluene.21. The process of claim 20, wherein the ratio of toluene to methanol isbetween 0.5:1 and 3:1.
 22. The process of claim 21, wherein the ratio oftoluene to methanol is about 1:1.
 23. The process of claim 1, whereinthe oxazolidine forming reagent is selected from the group consisting offormaldehyde, acetone, 2-methoxypropene, 2,2-dimethoxypropane,2,2-diethoxypropane and mixtures thereof.
 24. The process of claim 23,wherein the oxazolidine forming reagent is acetone.
 25. The process ofclaim 24, wherein the ratio of acetone to toluene is between about 0.5:1and 3:1.
 26. The process of claim 25, wherein the ratio of acetone totoluene is about 1:1.
 27. The process of claim 1, wherein theoxazolidine promoting base is selected from the group consisting ofpotassium carbonate, sodium carbonate, trimethylamine and triethylamine.28. The process of claim 27, wherein the oxazolidine promoting base ispotassium carbonate or triethylamine.
 29. The process of claim 1,wherein the compound of Formula VIII is


30. The process of claim 29, wherein the compound of Formula VIII is


31. The process of claim 1, wherein the third N-acylating agent is ofthe formula: formula R₆COR₇ wherein: R₆ is halo or C₁₋₆ alkoxy; and R₇is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ dihaloalkyl, C₁₋₆trihaloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cyclohaloalkyl, C₃₋₈cyclodihaloalkyl, C₃₋₈ cyclotrihaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₆ aralkyl, C₂₋₆ aralkenyl, C₂₋₆ heterocyclic, benzyl,phenyl or phenyl alkyl where the phenyl ring may be substituted by oneor two halogens, C₁₋₆ alkyl or C₁₋₆ alkoxy.
 32. The process of claim 31,wherein R₆ is Cl, Br, methoxy or ethoxy.
 33. The process of claim 32,wherein R₆ is Cl.
 34. The process of claim 31, wherein R₇ is CH₂Cl,CHCl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.
 35. The process ofclaim 34, wherein R₇ is CHCl₂.
 36. The process of claim 31, wherein thethird N-acylatating agent is selected from the group consisting ofmethyldichloroacetate, ethyldichloroacetate, dichloroacetylchloride,methylchloroacetate, ethylchloroacetate, chloroacetylchloride,methyltrichloroacetate, ethyltrichloroacetate, trichloroacetylchloride,methyldifluoroacetate, ethyldifluoroacetate, difluoroacetylchloride,methylfluoroacetate, ethylfluoroacetate, fluoroacetylchloride,methyltrifluoroacetate, ethyltrifluoroacetate, trifluoroacetylchloride,dichloroacetylbromide, difluoroacetylbromide, acetylchloride andacetylbromide and mixtures thereof.
 37. The process of claim 36, whereinthe third N-acylating agent is methyldichloroacetate ordichloroacetylchloride.
 38. The process of claim 37, wherein the thirdN-acylating agent is dichloroacetylchloride.
 39. The process of claim 1,wherein the third N-acylating base is selected from the group consistingof potassium carbonate, sodium carbonate, trimethylamine andtriethylamine.
 40. The process of claim 39, wherein the thirdN-acylating base is potassium carbonate or triethylamine.
 41. Theprocess of claim 40, wherein the molar equivalent ratio of the thirdN-acylating base to the compound of Formula VIII is between 1:1 and 3:1.42. The process of claim 41, wherein the molar equivalent ratio of thethird N-acylating base to the compound of Formula VIII is about 1.1:1.43. The process of claim 42, wherein the molar ratio of dichloroacetylchloride to the compound of Formula VIII is between about 1:1 and 3:1.44. The process of claim 43, wherein the molar ratio of dichloroacetylchloride to the compound of Formula VIII is about 1.1 to
 1. 45. Theprocess of claim 36, wherein the third N-acylation step is carried outat a temperature between 20-30° C.
 46. The process of claim 45, whereinthe third N-acylation reaction is complete within 2-4 hours.
 47. Theprocess of claim 1, wherein R₇ is CH₂Cl, CHCl₂, CCl₃, CH₂Br, CHBr₂,CBr₃, CH₂F, CHF₂, or CF₃.
 48. The process of claim 47, wherein R₇ isCHCl₂ or CHF₂.
 49. The process of claim 48, wherein R₇ is CHCl₂.
 50. Theprocess of claim 1, wherein the compound of Formula XII is:


51. The process of claim 50, wherein the compound of Formula XII is:


52. The process of claim 50, wherein the compound of Formula XII is:


53. The process of claim 52, wherein the compound of Formula XII is:


54. The process of claim 1, wherein the fluorinating agent is selectedfrom the group consisting ofN-(2-chloro-1,1,2-trifluoroethyl)diethylamine,N-(2-chloro-1,1,2-trifluor-oethyl)dimethylamine,N-(2-chloro-1,1,2-trifluoroethyl)dipropylamine,N-(2-chloro-1,1,2-trifluoroethyl)pyrrolidine,N-(2-chloro-1,1,2-trifluoroethyl)-2-methylpyrrolidine,N-(2-chloro-1,1,2-trifluoroethyl)-4-methylpiperazine,N-(2-chloro-1,1,2-trifluoroethyl)-morpholine,N-(2-chloro-1,1,2-trifluoroethyl)piperidine,1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, (Diethylamino)sulfurtrifluoride, Bis-(2-methoxyethyl)aminosulfur trifluoride,N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) andmixtures thereof.
 55. The process of claim 54, wherein the fluorinatingagent is N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine.
 56. Theprocess of claim 55, wherein the molar ratio ofN,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine to the compound ofFormula XII is between about 1:1 and 2:1.
 57. The process of claim 56,wherein the molar ratio ofN,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine to the compound ofFormula XII is about 1.5:1.
 58. The process of claim 57, wherein thefluorinating step is carried out at a temperature of from about 80° C.to about 110° C. and at a pressure of about 60 psi.
 59. The process ofclaim 1, wherein the organic solvent is selected from the groupconsisting of 1,2-dichloroethane, methylene chloride, chloroform,chlorobenzene, chlorinated hydrocarbons and mixtures thereof.
 60. Theprocess of claim 59, wherein the organic solvent is methylene chloride.61. The process of claim 1, wherein the compound of Formula XIII is


62. The process of claim 61, wherein the compound of Formula XIII is:


63. The process of claim 61, wherein the compound of Formula XIII is


64. The process of claim 63, wherein the compound of Formula XIII is


65. The process of claim 1, wherein the compound of Formula XI is:


66. The process of claim 65, wherein the compound is Florfenicol


67. The process of claim 1, wherein the acid catalyst is dilute aqueoushydrochloric acid, sulfuric acid, or phosphoric acid, methanesulfonicacid or p-toluene sulfonic acid.
 68. The process of claim 67, whereinthe acid catalyst is p-toluene sulfonic acid.
 69. The process of claim1, wherein the base catalyst is LiOH, NaOH, KOH, Li₂CO₃, Na₂CO₃, K₂CO₃,sodium methoxide, sodium ethoxide, potassium methoxide and potassiumethoxide.
 70. The process of claim 69, wherein the base catalyst isK₂CO₃.
 71. The process of claim 1, wherein the temperature of theselective hydrolysis is below 80° C.
 72. The process of claim 1, whereinmethylene chloride is the organic solvent for the selective hydrolysis.73. The process of claim 1, wherein the compound of Formula XI ispurified with a mixture of a C₁₋₁₀ alkyl mono, di or tri alcohol andwater to form the pure form of a compound of Formula XI.
 74. The processof claim 73, wherein the purification is carried out in a mixture ofmethanol, ethanol, propanol, iso-propanol, butanol, sec-butanol,t-butanol, pentanol, ethylene glycol, propylene glycol, butylene glycolor glycerin and water.
 75. The process of claim 74, wherein thepurification is carried out in a mixture of methanol, ethanol, propanol,isopropanol, butanol, sec-butanol, t-butanol, or pentanol and water. 76.The process of claim 75, wherein the purification is carried out in amixture of isopropanol and water.
 77. The process of claim 76, whereinthe ratio of isopropanol to water is between 1:5 and 5:1.
 78. Theprocess of claim 77, wherein the ratio of isopropanol to water is 1:1.79. The process of claim 78, wherein the dissolution temperature forpurification is the reflux point of 1:1 isopropanol and water.
 80. Theprocess of claim 73, wherein the purification reaction is cooled to10-30° C. to crystallize the desired compound.
 81. The process of claim80, wherein the purification reaction is cooled to about 20-25° C. tocrystallize the desired compound.